scholarly journals Salvia miltiorrhizaandCarthamus tinctoriusExtract Prevents Cardiac Fibrosis and Dysfunction after Myocardial Infarction by Epigenetically Inhibiting Smad3 Expression

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Jing Yang ◽  
Bo Wang ◽  
Na Li ◽  
Qingqing Zhou ◽  
Wenhui Zhou ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Growth Factor ◽  
Cardiac Function ◽  
Myocardial Fibrosis ◽  
Histone Methylation ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Salvia Miltiorrhiza ◽  
Left Ventricular

The incidence of cardiac dysfunction after myocardial infarction (MI) continues to increase despite advances in treatment. Excessive myocardial fibrosis plays a vital role in the development of adverse cardiac remodeling and deterioration of cardiac function. Understanding the molecular and cellular mechanism of the fibrosis process and developing effective therapeutics are of great importance.Salvia miltiorrhizaandCarthamus tinctoriusextract (SCE) is indicated for angina pectoris and other ischemic cardiovascular diseases in China. SCE has been shown to inhibit the platelet activation and aggregation, ameliorate ROS-induced myocardial necrosis by inhibiting mitochondrial permeability transition pore opening, and promote angiogenesis by upregulating the expression of vascular endothelial growth factor (VEGF). However, whether SCE has effect on cardiac fibrosis after MI is not fully clear. Here, a mouse model of MI was established to observe the effect of SCE upon survival, cardiac function, myocardial fibrosis, and inflammation. Quantitative PCR and western blot assays were used to determine the expression of genes related to transforming growth factor-β(TGF-β) cascade and inflammatory responsesin vivo. Additionally, the effects of SCE upon the collagen production, TGF-β/Smad3 (SMAD family member 3) signaling, and the levels of histone methylation in primary cardiac fibroblasts were detected. We found that SCE treatment significantly improved survival and left ventricular function in mice after MI. Inhibition of inflammation and fibrosis, as well as decreased expression of Smad3, was observed with SCE treatment. In TGF-β-stimulated cardiac fibroblasts, SCE significantly decreased the expression of collagen,α-smooth muscle actin (α-SMA), and Smad3. Furthermore, SCE treatment downregulated the levels of H3K4 trimethylation (H3K4me3) and H3K36 trimethylation (H3K36me3) at theSmad3promoter region of cardiac fibroblasts, leading to inhibition ofSmad3transcription. Our findings suggested that SCE prevents myocardial fibrosis and adverse remodeling after MI with a novel mechanism of suppressing histone methylation of theSmad3promoter and its transcription.

Activation of SIRT3 by resveratrol ameliorates cardiac fibrosis and improves cardiac function via the TGF-β/Smad3 pathway

2015 ◽  
Vol 308 (5) ◽  
pp. H424-H434 ◽  
Author(s):  
Tongshuai Chen ◽  
Jingyuan Li ◽  
Junni Liu ◽  
Na Li ◽  
Shujian Wang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cardiac Function ◽  
Calorie Restriction ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Transforming Growth Factor Β ◽  
Wild Type

Sirtuins [sirtuin (SIRT)1–SIRT7] mediate the longevity-promoting effects of calorie restriction in yeast, worms, flies, and mice. Additionally, SIRT3 is the only SIRT analog whose increased expression has been shown to be associated with longevity in humans. The polyphenol resveratrol (RSV) is the first compound discovered able to mimic calorie restriction by stimulating SIRTs. In the present study, we report that RSV activated SIRT3 in cardiac fibroblasts both in vivo and in vitro. Moreover, in wild-type mice, RSV prevented cardiac hypertrophy in response to hypertrophic stimuli. However, this protective effect was not observed in SIRT3 knockout mice. Additionally, the activation of SIRT3 by RSV ameliorated collagen deposition and improved cardiac function. In isolated cardiac fibroblasts, pretreatment with RSV suppressed fibroblast-to-myoblast transformation by inhibiting the transforming growth factor-β/Smad3 pathway. Therefore, these data indicate that the activation of SIRT3 by RSV could ameliorate cardiac fibrosis and improve cardiac function via the transforming growth factor-β/Smad3 pathway.

scholarly journals Retinoid X receptor agonists attenuates cardiomyopathy in streptozotocin-induced type 1 diabetes through LKB1-dependent anti-fibrosis effects

2020 ◽  
Vol 134 (6) ◽  
pp. 609-628 ◽  
Author(s):  
Dajun Chai ◽  
Xiaoyan Lin ◽  
Qiaowen Zheng ◽  
Changsheng Xu ◽  
Hong Xie ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Transforming Growth Factor Β ◽  
Underlying Mechanism ◽  
Left Ventricular ◽  
Retinoid X Receptor ◽  
Sprague Dawley

Abstract Diabetic cardiac fibrosis increases ventricular stiffness and facilitates the occurrence of diastolic dysfunction. Retinoid X receptor (RXR) plays an important role in cardiac development and has been implicated in cardiovascular diseases. In the present study, we investigated the effects of RXR agonist treatment on streptozotocin (STZ)-induced diabetic cardiomyopathy (DCM) and the underlying mechanism. Sprague–Dawley (SD) rats induced by STZ injection were treated with either RXR agonist bexarotene (Bex) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with high glucose (HG) with or without the indicated concentration of Bex or the RXR ligand 9-cis-retinoic acid (9-cis-RA). The protein abundance levels were measured along with collagen, body weight (BW), blood biochemical indexes and transforming growth factor-β (TGF-β) levels. The effects of RXRα down-regulation by RXRα small interfering RNA (siRNA) were examined. The results showed that bexarotene treatment resulted in amelioration of left ventricular dysfunction by inhibiting cardiomyocyte apoptosis and myocardial fibrosis. Immunoblot with heart tissue homogenates from diabetic rats revealed that bexarotene activated liver kinase B1 (LKB1) signaling and inhibited p70 ribosomal protein S6 kinase (p70S6K). The increased collagen levels in the heart tissues of DCM rats were reduced by bexarotene treatment. Treatment of CFs with HG resulted in significantly reduced LKB1 activity and increased p70S6K activity. RXRα mediated the antagonism of 9-cis-RA on HG-induced LKB1/p70S6K activation changes in vitro. Our findings suggest that RXR agonist ameliorates STZ-induced DCM by inhibiting myocardial fibrosis via modulation of the LKB1/p70S6K signaling pathway. RXR agonists may serve as novel therapeutic agents for the treatment of DCM.

scholarly journals EphrinB2 Regulates Cardiac Fibrosis Through Modulating the Interaction of Stat3 and TGF-β/Smad3 Signaling

2017 ◽  
Vol 121 (6) ◽  
pp. 617-627 ◽  
Author(s):  
Sheng-an Su ◽  
Du Yang ◽  
Yue Wu ◽  
Yao Xie ◽  
Wei Zhu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Left Ventricular ◽  
Intramyocardial Injection

Rationale: Cardiac fibrosis is a common feature in left ventricular remodeling that leads to heart failure, regardless of the cause. EphrinB2 (erythropoietin-producing hepatoma interactor B2), a pivotal bidirectional signaling molecule ubiquitously expressed in mammals, is crucial in angiogenesis during development and disease progression. Recently, EphrinB2 was reported to protect kidneys from injury-induced fibrogenesis. However, its role in cardiac fibrosis remains to be clarified. Objective: We sought to determine the role of EphrinB2 in cardiac fibrosis and the underlying mechanisms during the pathological remodeling process. Methods and Results: EphrinB2 was highly expressed in the myocardium of patients with advanced heart failure, as well as in mouse models of myocardial infarction and cardiac hypertrophy induced by angiotensin II infusion, which was accompanied by myofibroblast activation and collagen fiber deposition. In contrast, intramyocardial injection of lentiviruses carrying EphrinB2-shRNA ameliorated cardiac fibrosis and improved cardiac function in mouse model of myocardial infarction. Furthermore, in vitro studies in cultured cardiac fibroblasts demonstrated that EphrinB2 promoted the differentiation of cardiac fibroblasts into myofibroblasts in normoxic and hypoxic conditions. Mechanistically, the profibrotic effect of EphrinB2 on cardiac fibroblast was determined via activating the Stat3 (signal transducer and activator of transcription 3) and TGF-β (transforming growth factor-β)/Smad3 (mothers against decapentaplegic homolog 3) signaling. We further determined that EphrinB2 modulated the interaction between Stat3 and Smad3 and identified that the MAD homology 2 domain of Smad3 and the coil–coil domain and DNA-binding domain of Stat3 mediated the interaction. Conclusions: This study uncovered a previously unrecognized profibrotic role of EphrinB2 in cardiac fibrosis, which is achieved through the interaction of Stat3 with TGF-β/Smad3 signaling, implying a promising therapeutic target in fibrotic diseases and heart failure.

scholarly journals Manuscript title Microparticles Containing MiR-625-5p In Coronary Artery Reduce Myocardial Fibrosis After Myocardial Infarction

2021 ◽  
Author(s):  
Ningxin Wen ◽  
Qi Zhang ◽  
Xuan Wu ◽  
Jianing Gao ◽  
Yangkai Xu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
High Mobility ◽  
Coronary Intervention ◽  
Thrombus Aspiration ◽  
St Segment Elevation ◽  
Emergency Percutaneous Coronary Intervention

Abstract PurposeBlood from infarct-related arteries obtained by thrombus aspiration is good material for studying the local microenvironment of blood vessels in myocardial infarction. Here, we aimed to observe the effects of intracoronary microparticles (MPs) on cardiac fibrosis and to find associated microRNAs in MPs.MethodsBlood samples were collected from patients with ST-segment elevation myocardial infarction who underwent emergency percutaneous coronary intervention, and sub-supersonic centrifugation was used to separate the MPs.ResultsWe found that rats treated with intracoronary MPs showed better cardiac function after myocardial infarction compared with rats treated with PBS control or peripheral MPs. RNA microarray analysis indicated that microRNAs, especially miR-625-5p, may play a role in the process. Supplementation with miR-625-5p inhibited proliferation of cardiac fibroblasts and myocardial fibrosis in a mouse myocardial infarction model. ConclusionOur findings indicate that plasma MPs in infarct-related arteries in patients with acute myocardial infarction can inhibit myocardial fibrosis and improve cardiac function, with a process mediated by miR-625-5p and HMGA1 (high mobility group AT-hook 1). The current study may provide a possible reference for thrombus aspiration standard.

Abstract 13810: TT-00920, a Clinical Stage Novel Phosphodiesterase 9 Inhibitor, Protects Against Heart Failure in a Rat Model of Myocardial Infarction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Zejuan Sheng ◽  
Xiaoyan Qiang ◽  
Guoyu Li ◽  
Huimin Wang ◽  
Wenxin Dong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Function ◽  
Rat Model ◽  
Cardiac Fibrosis ◽  
Clinical Stage ◽  
Left Ventricular ◽  
Guanosine Monophosphate ◽  
Therapeutic Effects ◽  
Dependent Manner

Introduction: Phosphodiesterase 9 (PDE9) controls natriuretic-peptide-stimulated cyclic guanosine monophosphate in cardiac myocytes and is stongly upregulated in human heart failure, suggesting its potential as a promising therapeutic target in heart failure. Here we investigated the potential effects of TT-00920, a clinical stage novel and highly selective PDE9 inhibitor, on heart failure in a rat model of myocardial infarction. Methods: Myocardial infarction was induced by left anterior descending coronary artery (LAD) ligation in male Sprague Dawley rats. After 4-week treatment of vehicle, LCZ696, TT-00920, or TT-00920/Valsartan by oral gavage, efficacy was assessed by echocardiography and cardiac histopathology. Results: TT-00920 had remarkably improved cardiac function, protected against cardiac remodeling and fibrosis in a dose-dependent manner. TT-00920/Valsartan combination showed superior beneficial efficacy when compared to TT-00920 or LCZ696 single agent.Figure 1. TT-00920 improved cardiac function and ventricular remodeling.Figure 2. TT-00920 attenuated cardiac fibrosis in peri-infarct zone. Conclusions: TT-00920 reversed LAD-induced left ventricular dysfunction and remodeling, supporting its potential as a novel therapeutic agent for heart failure. The superior efficacy of TT-00920/Valsartan combination suggests that TT-00920 and renin-angiotensin-aldosterone system inhibitors may have additive therapeutic effects in heart failure.TT-00920 is currently being evaluated in Phase 1 clinical study for safety, tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers (NCT04364789).

Abstract 5362: Inhibition Of The Epidermal Growth Factor Receptor Transactivation By The Angiotensin II Type I Receptor Prevents Compensatory Cardiac Hypertrophy And Worsens Cardiac Function Following Myocardial Infarction

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Jonathan Galeotti ◽  
Chiao Po Hsu ◽  
Peiyong Zhai ◽  
Junichi Sadoshima
Keyword(s):  
Myocardial Infarction ◽  
Epidermal Growth Factor Receptor ◽  
Angiotensin Ii ◽  
Growth Factor ◽  
Cardiac Function ◽  
Growth Factor Receptor ◽  
Left Ventricular ◽  
Type I ◽  
Epidermal Growth ◽  
Tibia Length

The angiotensin II type I receptor (AT1R) has been shown to activate the epidermal growth factor receptor (EGFR). However, the downstream effects of this activation have not yet been elucidated in the heart. To examine the function of the AT1R-EGFR pathway, we have created an AT1R mutant in which amino acid 319 is mutated from tyrosine to phenylalanine (Y319F). The Y319F mutant lacks the ability to transactivate the EGFR. We generated transgenic lines overexpressing either wild type AT1R (Tg-WT) or Y319F (Tg-Y319F) only in the heart with similar levels of overexpression, and evaluated the contribution of the AT1R-EGFR pathway to cardiac responses against stress. Under baseline conditions at 3 months of age, cardiac function of Tg-WT and Tg-Y319F was not significantly different from non-transgenic mice (NTg) except that Tg-WT showed mild left ventricular hypertrophy. To examine the role of the AT1R-EGFR pathway under stress, we induced myocardial infarction (MI) by permanently ligating the left anterior descending coronary artery. Four weeks after MI, increases in heart weight/tibia length (Tg-WT, Tg-Y319F, NTg: 12.57, 10.11, 9.96, p<0.05 vs Tg-WT) and left ventricular myocyte cross sectional area (35, 5, 29% vs sham, p<0.05) were significantly attenuated in Tg-Y319F compared to Tg-WT. Fibrosis was also milder in Tg-Y319F than in Tg-WT (10.7% vs 22.9%). These results suggest that the AT1R-EGFR pathway plays an important role in mediating LV hypertrophy and fibrosis after MI. Interestingly, however, echocardiographic measurement showed that Tg-Y319F have impaired LV ejection fraction (Tg-WT, Tg-Y319F, NTg: 51, 19, 44%, p<0.05) and %fractional shortening (21.4, 6.7, 17.7%, p<0.05) compared with Tg-WT or NTg. Tg-Y319F showed an increase in mortality in days 0–28 following MI, when compared to Tg-WT and NTg (35, 67, 30%, p<0.5). Additionally, lung weight/tibia length was increased in Tg-Y319F (11.3, 24.7, 16.1, p<0.05) These results suggest that the lack of EGFR activation causes cardiac dysfunction after MI. In summary, transactivation of the EGFR following MI may play a compensatory role, thereby protecting the heart from further deterioration of cardiac function. This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).

scholarly journals Thymosin-β4 prevents cardiac rupture and improves cardiac function in mice with myocardial infarction

2014 ◽  
Vol 307 (5) ◽  
pp. H741-H751 ◽  
Author(s):  
Hongmei Peng ◽  
Jiang Xu ◽  
Xiao-Ping Yang ◽  
Xiangguo Dai ◽  
Edward L. Peterson ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cell Survival ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Capillary Density ◽  
Left Ventricular ◽  
Cardiac Rupture ◽  
Gelatinolytic Activity ◽  
P53 Expression

Thymosin-β4 (Tβ4) promotes cell survival, angiogenesis, and tissue regeneration and reduces inflammation. Cardiac rupture after myocardial infarction (MI) is mainly the consequence of excessive regional inflammation, whereas cardiac dysfunction after MI results from a massive cardiomyocyte loss and cardiac fibrosis. It is possible that Tβ4 reduces the incidence of cardiac rupture post-MI via anti-inflammatory actions and that it decreases adverse cardiac remodeling and improves cardiac function by promoting cardiac cell survival and cardiac repair. C57BL/6 mice were subjected to MI and treated with either vehicle or Tβ4 (1.6 mg·kg−1·day−1 ip via osmotic minipump) for 7 days or 5 wk. Mice were assessed for 1) cardiac remodeling and function by echocardiography; 2) inflammatory cell infiltration, capillary density, myocyte apoptosis, and interstitial collagen fraction histopathologically; 3) gelatinolytic activity by in situ zymography; and 4) expression of ICAM-1 and p53 by immunoblot analysis. Tβ4 reduced cardiac rupture that was associated with a decrease in the numbers of infiltrating inflammatory cells and apoptotic myocytes, a decrease in gelatinolytic activity and ICAM-1 and p53 expression, and an increase in the numbers of CD31-positive cells. Five-week treatment with Tβ4 ameliorated left ventricular dilation, improved cardiac function, markedly reduced interstitial collagen fraction, and increased capillary density. In a murine model of acute MI, Tβ4 not only decreased mortality rate as a result of cardiac rupture but also significantly improved cardiac function after MI. Thus, the use of Tβ4 could be explored as an alternative therapy in preventing cardiac rupture and restoring cardiac function in patients with MI.

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